Summary Safety Review - Cyclin-dependent Kinase Inhibitors (abemaciclib, palbociclib and ribociclib) and HMG-CoA Reductase Inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin) (Statins) - Assessing the Potential Risk of Rhabdomyolysis Due to Drug Interaction

Cyclin-dependent kinase inhibitors (CDKIs) (abemaciclib-, palbociclib- and ribociclib-containing products) and HMG-CoA reductase inhibitors, more commonly known as statins (atorvastatin-, fluvastatin-, lovastatin-, pravastatin-, rosuvastatin- and simvastatin-containing products)

Rhabdomyolysis (muscle breakdown) due to the drug interaction (when one drug affects how another drug behaves in the body) between CDKIs and statins

• Health Canada’s review found a possible link between the risk of rhabdomyolysis and the drug interaction between CDKIs and statins.

• Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for all CDKIs to include the risk of rhabdomyolysis due to the drug interaction with statins. Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

Health Canada reviewed the potential risk of rhabdomyolysis and the drug interaction between CDKIs and statins. The safety review was triggered by the European Medicines Agency (EMA)’s investigation of the risk with palbociclib and statins.

Rhabdomyolysis is a rare and potentially life-threatening condition in which muscles break down and their contents are released into the blood stream. This can lead to organ damage, such as kidney failure. Rhabdomyolysis is a known risk associated with statins. Some drugs may increase the body’s exposure to statins, thereby increasing the patient’s risk of statin-related rhabdomyolysis. Though the risk of rhabdomyolysis is known and well labelled for statins, this review investigated the potential risk of rhabdomyolysis due to the drug interaction between CDKIs and statins.

• Cyclin-dependent kinase inhibitors are a class of prescription drugs authorized for sale in Canada for the treatment of a specific, but common, type of breast cancer.

• Statins are prescription drugs authorized for sale in Canada, to be used along with diet, to lower cholesterol and triglyceride (fat) levels in the blood, and to reduce the risk of heart attack or stroke in patients with risk factors for heart problems.

• Cyclin-dependent kinase inhibitors have been marketed in Canada since 2016. There are currently 3 CDKIs available in Canada (abemaciclib, palbociclib and ribociclib) as single-ingredient oral tablets and oral capsules under different brand names and generic versions.

• Statins have been marketed in Canada since 1995. There are currently 6 statins available in Canada (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin) as single-ingredient and fixed-combination oral tablets and oral capsules under different brand names and generic versions.

• In the last 5 years, more than 270,00 prescriptions for CDKIs were dispensed in Canada. Palbociclib represented close to 80% of those prescriptions. In the same period, approximately 237 million prescriptions for statins were dispensed in Canada. Rosuvastatin and atorvastatin represented over 90% of those prescriptions.

• Health Canada reviewed the available information provided by the manufacturers, as well as from searches of the Canada Vigilance database^a and the scientific literature.

• Health Canada reviewed 13 cases (1 Canadian and 12 international) of rhabdomyolysis in patients taking both a CDKI (palbociclib or ribociclib) and statin (rosuvastatin or simvastatin). All 13 cases were found to be possibly linked to the drug interaction between CDKIs and statins. There were no deaths reported among the cases.

• In all 13 cases, patients had been on statin therapy prior to starting CDKI therapy. In 8 of those cases, statin therapy was ongoing without reported rhabdomyolysis for over 1 year prior to the start of CDKI therapy. In 6 of these 8 cases, rhabdomyolysis occurred within 30 days of the addition of a CDKI, which suggests the possibility that CDKI introduction increased the body’s exposure to statins, leading to rhabdomyolysis.

• While a drug interaction between CDKIs and statins is not currently labelled for either class of product, information contained in the CPM concerning how they work in the body supports the possibility of a drug interaction.

• Health Canada also reviewed a study that investigated the potential interaction between palbociclib and atorvastatin using computer simulation. This study suggested that 125 mg/day of palbociclib could moderately increase the exposure of 40 mg/day atorvastatin in healthy volunteers, thereby potentially increasing the risk of rhabdomyolysis.

• Although observed rhabdomyolysis cases were limited to the combined administration of palbociclib or ribociclib, and rosuvastatin or simvastatin, the totality of evidence supports the precautionary conclusion that rhabdomyolysis is a potential risk due to a drug interaction between CDKIs and statins.

• Health Canada’s review of the available information found a possible link between rhabdomyolysis and the drug interaction between CDKIs and statins.

• Health Canada will work with the manufacturers to update the CPM for all CDKIs to include the risk of rhabdomyolysis due to the drug interaction with statins.

• Health Canada will also inform healthcare professionals about this update through a Health Product InfoWatch communication.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to the use of CDKIs or statins, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving the combined administration of CDKIs and statins, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific and medical literature, Canadian and international information and what is known about the use of CDKIs and statins both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Canadian reports can be accessed through the Canada Vigilance Online Database.